Non-Invasive Vagal Nerve Stimulation in Patients with Opioid Use Disorders

Treatment of Opioid Use Disorders (OUDs) includes medications with effects on opioid receptors such as
buprenorphine, but access is limited for many patients and others are opposed to treating addictions with
medications that have opioid agonist properties. Naltrexone is an opioid antagonist that is more acceptable for
many patients, and recent studies show it to be equivalent in efficacy. Initiation of treatment with long-acting
naltrexone, however, requires a period of abstinence of about seven days during which time patients suffer
from intense symptoms of withdrawal with a risk of relapse that can lead to overdose-related death. Opioids
have an inhibitory effect on norepinephrine and the sympathetic nervous system, and many symptoms of
withdrawal are driven by rebound activation of these systems. Dopaminergic systems in brain areas including
ventral striatum (nucleus accumbens) and medial prefrontal cortex (anterior cingulate) play an important role in
opioid addiction, craving and relapse, as do increases in inflammation. This project will assess a form of
neuromodulation involving non-invasive electrical stimulation of the vagus nerve that may play a useful role
during the period of opioid withdrawal before the initiation of long-term naltrexone treatment in blocking
norepinephrine, sympathetic, and inflammatory responses and enhancing peripheral parasympathetic and
central brain function in areas modulating drug craving (ventral striatum, anterior cingulate). Our preliminary
data on the effects of non-invasive Vagal Nerve Stimulation (nVNS) on stress response in traumatized human
subjects and patients with posttraumatic stress disorder (PTSD) show that nVNS reliably blocks peripheral
sympathetic and enhances parasympathetic function, reduces inflammatory responses (interleukin-6, or IL-6),
and enhances central brain responses (anterior cingulate) to stress. We now propose to apply this technology
to the treatment of patients with OUDs. Following verification using modelling and determination of optimal
dosing parameters, we will use these parameters to assess effects of nVNS versus sham stimulation on opioid
craving, peripheral autonomic, cardiovascular, inflammatory, and brain functional responses measured with
High-Resolution Positron Emission Tomography (HR-PET) and radiolabeled water to videos of drug cues in
recently treated patients with OUDs. Based on the outcome of this research, we will proceed to the UH3
phase, which will involve a randomized, sham-controlled trial of nVNS in patients with OUDs during the one to
two week period of opioid withdrawal followed by assessment of craving, HR-PET imaging of both brain
function and brain dopaminergic function, and assessment of peripheral autonomic, cardiovascular and
inflammatory responses in conjunction with administration of nVNS or sham. We hypothesize that nVNS will
reduce opioid craving and inflammatory, peripheral autonomic and cardiovascular responses and enhance
brain responses (anterior cingulate function and dopamine function in ventral striatum), and promote
successful conversion to long-acting naltrexone, in patients with OUDs.

Grant Number: 5UH3DA048502-04
NIH Institute/Center: NIH
Principal Investigator: James Bremner